U.S. patent number 4,657,553 [Application Number 06/758,060] was granted by the patent office on 1987-04-14 for chemical substances.
Invention is credited to David E. M. Taylor.
United States Patent |
4,657,553 |
Taylor |
April 14, 1987 |
Chemical substances
Abstract
The invention provides soft tissue implants, for the replacement
and/or enhancement of human or animal soft tissue, composed of a
hydrogel comprising (a) a gelable polysaccharide and/or protein or
polypeptide and (b) a polymer of a hydrophilic acrylic and/or
methacrylic acid derivative.
Inventors: |
Taylor; David E. M. (London
WC2A 3PN, GB2) |
Family
ID: |
10564323 |
Appl.
No.: |
06/758,060 |
Filed: |
July 23, 1985 |
Foreign Application Priority Data
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Jul 24, 1984 [GB] |
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8418772 |
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Current U.S.
Class: |
623/8 |
Current CPC
Class: |
A61L
27/26 (20130101); A61L 27/52 (20130101); A61L
27/26 (20130101); A61L 27/52 (20130101); C08L
33/26 (20130101); C08L 5/12 (20130101); A61L
27/26 (20130101); A61L 27/52 (20130101); A61F
2/12 (20130101); A61F 2/08 (20130101); A61L
27/26 (20130101); C08L 33/26 (20130101) |
Current International
Class: |
A61L
27/52 (20060101); A61L 27/00 (20060101); A61L
27/26 (20060101); A61F 002/00 () |
Field of
Search: |
;623/66,7,8,11,16
;260/123.7 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: McNeill; Gregory E.
Attorney, Agent or Firm: Bernard, Rothwell & Brown
Claims
I claim:
1. Soft tissue implants, for the replacement and/or enhancement of
human or animal soft tissue, composed of a hydrogel comprising (a)
a gelable polysaccharide and/or protein or polypeptide and (b) a
polymer of a hydrophilic acrylic and/or methacrylic acid
derivative.
2. Implants as claimed in claim 1 in which the hydrogel comprises
(a) agar-agar (agarose) and (b) cross-linked polyacrylamide.
3. Implants as claimed in claim 2 in which the ratio of component
(a) to component (b) is in the range 1:3 to 1:4.
4. Implants as claimed in claim 1 which the water content of the
hydrogel is 95 to 98% by weight.
5. Implants as claimed in claim 1 in the form of breast-shaped
prostheses.
6. A method of replacement and/or enhacement of human or animal
soft tissue which comprises implanting a prosthesis composed of a
hydrogel as defined in claim 1 is implanted in a soft tissue region
of the human or animal body.
7. A method as claimed in claim 6 in which the prosthesis is breast
shaped and is implanted below the skin and/or other tissue of the
human female breast to replace and/or enhance the fatty tissue of
the breast.
8. A method as claimed in claim 6 in which the prosthesis is
implanted intramuscularly to replace muscle removed by injury
and/or surgery.
Description
This invention relates to aqueous gels and their use as soft tissue
implants.
Soft tissue implantation is now a relatively new surgical technique
for replacement of fatty tissues, fibrous tissue sheets and/or
muscle removed by surgery or for remodelling soft tissues such as
the breasts if these are thought to be inadequate. The materials
which have been used hitherto have included silicone rubber and
expanded polytetrafluorethylene. Certain gels having a consistency
and firmness resembling that of normal fatty tissue have been
proposed but are of inadquate mechanical strength. A prosthesis of
calculated size and shape prepared from such material is carefully
inserted beneath intact skin or muscle to produce the required
reshaping and the incision is then closed.
In the period immediately after healing of the incisions, the
implant gives a realistic impression of healthy human tissue
beneath the overlying skin. However, tissue reaction commonly sets
in quite rapidly, with the progressive formation of a fibrous
interface between the prosthesis and the surrounding tissue. Such
fibrous tissue is commonly either more rigid than the implant or is
contractile and so compresses the implant with a consequent
increase in its rigidity. This may even, for a time, be thought to
enhance the desired remodelling, particularly in the case of
breasts, where a firm shape is valued. However, the rigidity of the
prosthesis eventually becomes noticeable in producing pronounced
ridges and the lack of resilience also emphasises the unnatural
appearance of the reshaped breast. This is generally found to be
psychologically disturbing to the patient.
Indeed, reshaping of breasts by soft tissue implant surgery has met
with criticism partly because the eventual rigidity of the implant
effectively masks any hardening due to carcinoma, so making routine
testing for breast cancer difficult or impossible.
We have now found a material which is particularly suitable for use
in soft tissue implantation. After subcutaneous, intramuscular and
intraperitonal implantation in experimental animals over a six
month period or longer, the tissue reaction which has been observed
is significantly less than that with the common implant materials
in clinical use.
Thus, in general, the capsule surrounding the implant is thinner
than that found with comparable implants of silicone rubber and
expanded polytetrafluorethylene and the collagen in the capsule is
well packed and structured, in general being more flexible and less
attached to surrounding tissue. The incidence of fibroblasts,
mononuclear cells and giant cells is also lower.
The present invention extends to soft tissue implants composed of a
hydrogel comprising (a) a gelable polysaccharide and/or protein or
polypeptide and (b) a polymer of a hydrophilic acrylic or
methacrylic acid derivative.
Such gels can readily be prepared having a critical surface tension
and surface free energy approximating to the optimum for
biotolerance. The contact angle with water is small being less than
30.degree.. This is, in part, because the water content of such a
hydrogel can be very high, for example in the range 95 to 98% by
weight, preferably about 97%. Thus, the solid matrix of the gel may
constitute only 2 to 5% by weight of the gel, preferably about
3%.
The hydrogel preferably comprises the gelable polysaccharide,
polypeptide or protein and the (meth)acrylic polymer in the ratio
range 9:1 to 1:9 by weight, preferably in the range 1:9 to 4:6.
The hydrogels are preferably of the type described in United
Kingdom Patent Specification No. GB-A-1594389. Thus the hydrophilic
acrylic or methacrylic acid derivative is preferably an amide, more
preferably acrylamide, or an ester with an alkanol, optionally a
polyol, especially preferably a C.sub.1-6 alkanol such as methanol
or ethanol. Conventional bi- or polyfunctional cross-linking agents
such as N,N'-methylene-bis-acrylamide may be used to cross-link the
polymer.
The gelable polysaccharide is preferably agarose or agar-agar while
amongst gelable proteins and polypeptides, gelatine is
preferred.
In general, the most preferred hydrogels comprise (a) agar-agar
together with (b) polyacrylamide cross-linked with about 2% by
weight of N,N'-methylene bis-acrylamide, advantageously in the
ratio range 1:3 to 1:4, preferably about 1:3.5. This gel, when
fully swollen with water, contains about 96.5% by weight of water.
A gel of this type is now commercially available from Geistlich
Pharma of Wolhusen, Switzerland under the Registered Trade Mark
Geliperm.
It should be noted that agar-agar gels are commonly hard and
brittle. On the other hand, polyacrylamide gels, even when
cross-linked, are relatively soft and tacky. The above hydrogels
containing both these materials are, however, nontacky and of a
consistency remarkably close to that of the human tissues to be
replaced or remodelled.
Thus, the elastic modulus of the hydrogel material is in the same
range as that of the tissues it is designed to replace. In order to
achieve such an elastic modulu for silicone breast implants it is
necessary to employ a composite of an outer case of silicone rubber
containing silicone fluid. Expanded polytetrafluoroethylene is a
firmer although stronger material which is primarily used to
replace fascia and other sheet-like tissues.
The above hydrogels are also surprisingly strong and are in general
well able to withstand the stresses to which they are subjected by
body movement. Many previously used materials have shown some
tendency to break up under such stresses. The tensile strength at
break of a test strip of the preferred agar-agar/polyacrylamide gel
3.3 mm thick and 20 mm wide is 2-3 Newtons Elongations in the range
75 to 150% have been observed, even after storage of the material
for as long as 2.5 years. It seems possible that the polyacrylamide
may prevent crystallisation of the agarose, thus avoiding hardness,
while some measure of cross-linking may take place between the agar
and the polyacrylamide which increases the strength of the
material. However, if necessary, as described in United Kingdom
Patent Specification No. GB-A-1594389, strengthening reinforcements
can be incorporated in the gel, for example, fibres or meshes.
The hydrogels for use according to the invention may be prepared in
the way described in the above United Kingdom Patent Specification.
Thus, an aqueous solution of the gelable polysaccharide or protein
or polypeptide may be mixed with an aqueous solution of the
hydrophilic monomer to be polymerised, e.g. acrylamide, if desired
together with cross-linking agent, and polymerisation may then be
initiated. The two components thus form a substantially homogenous
matrix or lattice. The hydrogel so formed is then washed thoroughly
to remove all unreacted materials. During this washing step, the
hydrogel will normally absorb water until it reaches equilibrum. It
will be appreciated that when a prothesis of such material is
implanted, it will reach equilibrum with the water and dissolved
materials in the surrounding tissue fluid. It is possible
therefore, that the prosthesis could be prepared from hydrogel
containing less than the equilibrum quantity of water and that a
moderate increase in volume could be allowed to take place
subsequently by equilibration with water from the surrounding
tissues. United Kingdom Patent Specification No. GB-A-203042
describes the removal of water from the hydrogels of United Kingdom
Patent Specification No. GB-A-1594389 and the present invention
includes implantation of hydrogels having less than the equilibrum
concentration of water prepared by such methods.
If desired, the water in the prosthesis may contain dissolved
substances, such as salts, e.g. to render the gel isotonic, as well
as antibacterials to reduce infection and/or antiinflammatories to
reduce inflammation following surgery.
The preparation of the prosthesis from the hydrogel may be
accomplished by shaping techniques employed with previously used
materials. Thus, for example, in the case of breast prostheses,
moulds can be made in which a hydrogel implant of the desired
profile may be cast. In general, a series of standard sizes may be
available for selection of the appropriate implant by the surgeon.
In the case of plastic surgery, for example of the face, implants
may comprise strips of the material cut to size by the surgeon
during surgery. In the case of muscle implants, relatively large
blocks of the hydrogel may be shaped by the surgeon immediately
prior to implantation.
It should be noted that while soft tissue implants have previously
been introduced as a replacement and/or enhancement of fatty tissue
or fascia tissue, no material has previously been successful for
replacement of muscle tissue. We have surprisingly found that
significant blocks of muscle tissue can successfully be replaced
and after recovery of the subject from surgery, the implant is
barely palpable and hypertrophy of surrounding muscle may
compensate for the lost muscle tissue. The formation of scar tissue
is minimal, so that there is little or no interference by the
prosthesis with normal muscular activity.
In the case of breast prostheses, conventional surgical techniques
may be used. Thus, for replacement, e.g. after mastectomy, the
outer dermal tissues will have been cut in such a way as to
minimise unsightly scarring and after removal of the original fatty
tissue, an appropriate hydrogel prosthesis may be slipped into
place and the incesions closed. For enhancement, it may be
preferable to implant the prosthesis behind the original breast
tissue, between the major and minor pectoral muscles.
The following Example is given by way of illustration only:
EXAMPLE
20 g of agar-agar are suspended under agitation in 880 g of
deionized water and heated to 95.degree. C. until complete
dissolution. 1 l of a second aqueous solution containing 70 g of
acrylamide and 1.84 g of N,N'-methylene-bis-acrylamide is prepared
at ambient temperature and added to the first solution with
thorough mixing. Under continued agitation, 2.2 g of
N,N,N',N'-tetrakis-(2-hydroxypropyl)-ethylene diamine dissolved in
60 g of water and then 1.26 g of ammonium peroxidisulfate dissolved
in 40 g of water are added.
The mixture has a temperature between 50.degree. C. and 55.degree.
C. and begins to polymerize immediately. After 10 minutes the gel
point is reached. The batch is allowed to cool down overnight
during which time polymerization is completed.
The gel is freed from soluble impurities by washing with pure
flowing water for 24 hours. With this washing the gel swells to
135% of its original weight. This product is now commercially
available under the name Geliperm from Geistlich Pharma of
Wolhusen, Switzerland.
The gel may then be shaped to form a prosthesis and used as a
tissue implant by known surgical techniques.
(a) Biotolerance Studies
Experiments have been carried out in the rat; to assess
biotolerance after six week implantation, to assess biotolerance
after six months, to assess possible long term biodegradation, and
to determine whether delayed hypersensitivity occurred.
Material and Methods
The Geliperm was in strip form and was implanted in the fully
hydrated state. Test implants were approximately 5.times.5.times.3
mm.
The experimental animals were adult PortonWistar rats of weight
250-350 g.
The six week and six months biotolerance studies were carried out
on 8 and 10 animals respectively, while the other two studies each
involved 6 animals. In all studies three implant sites were used,
intramuscular into the sacrospinalis, subcutaneous into the lateral
abdominal wall and intraperitoneal.
For the biotolerance studies two control materials were also
studied after six weeks implantation in 8 animals each:
polydimethylsiloxane (Silastic (Registered Trade Mark) Dow Corning
Inc.) and expanded microporous polytetrafluoraethylene (Gore-Tex
(Registered Trade Mark) W. L. Gore Associates). These were selected
as materials of proven good biotolerance in the intended field of
application and in current clinical use.
Biotolerance was assessed by quantitative histology for capsule
thickness, cellular infiltrate density and collagen
organisation.
For the biodegradation studies the test samples of Geliperm were
dehydrated and weighed under sterile conditions, then rehydrated
before implantation. At the end of the test period the recovered
implants were again dehydrated and weighed. This was to avoid
errors due to variation of water-content of the hydrogel.
For the delayed hypersensitivity test after six weeks implantation
at the three standard sites, the skin of the back was shaven and
test patches of Geliperm and a control moist gauze swab applied to
the back for 72 hours. The animal was then sacrificed and after
macroscopic examination the skin of the back was assessed
histologically for oedema, inflammation and lymphocyte or other
cellular infiltration.
Results
There was no macroscopically inappropriate response to Geliperm at
either six weeks or six months implantation: indeed of the
peritoneal implants many were free within the peritoneal cavity,
although encapsulated. All the six week control materials were
invested in bowel or peritoneum and strongly bound with
adhesions.
At 6 months the capsule thickness around the Geliperm was not
significantly different from that at six weeks being less than 50
microns. The collagen of the capsule was well packed and oriented
parallel to the implant interface. The capsule thickness was
significantly less than that surrounding the Silastic implants and
slightly less than that of the Gore-tex implants. The incidence of
fibroblasts, monocuclear cells and giant cells was lower in the
case of Geliperm than the control materials.
There was no evidence of significant biodegradation at three months
and no evidence of skin sensitivity developing.
(b) Reconstructive Surgery Studies: rats
Two studies were carried out in the rat: in the first a large
muscle defect in the sacrospinalis muscle in the lumbar region was
replaced with polyacrylamideagarose and the fascia closed over it,
while in the second a pair of "breast implants" were placed
subcutaneously or retropectoral in the anterior thoracic region.
The muscle implants were studied after six weeks and six months.
There was no functional disability in the animals and the implant
site was not palpable through the skin in life. There was a minimal
fibrous capsule (<70 um) around the implant and there appeared
to be hypertrophy of surrounding muscle. The "breast implants" also
showed little fibrous capsule formation and had not changed
appreciably in consistance when examined at up to three months
after implantation. With both long term implants there was little
evidence of a chronic inflammatory reaction persisting and giant
cells were virtually absent.
(b) Reconstructive Surgery Studies: dogs
In a pilot study large (26 and 53 g) defects of the sacrospinalis
muscle were made in 2 dogs and replaced with Geliperm shaped from
13 mm thick sheets. Both healed well and showed good resolution.
The defects were not palpable and the animals had a normal range
and strength of movement.
In a further dog two subcutaneous blocks, each of about 50 g in
weight, of Geliperm were placed subcutaneously in the back, one
superficial and the other deep to platysma. After two months the
wounds were well healed with no residual induration. The most
superficial implant was palpable, but soft and mobile with the
subcutaneous tissue. The implant deep to platysma could be
distinguished by palpation.
* * * * *